The program objective is to define the biochemical basis of certain inherited disorders of the human nervous system, with emphasis on those which affect myelin: 1. A Variant Form of Metachromatic Leukodystrophy (MLD). In this form of MLD the accumulation of sulfatide, mucopolysaccharides (MPS), and deficient activities of arylsulfatases A,B & C have been demonstrated by Autin et al. We have shown that there is also accumulation of steroid sulfate and deficient activity of the steroid sulfatases: (a) We will attempt to solubilize and purify normal human arylsulfatase C and steroid sulfatase. If we can do this, we will determine whether tissues from the MLD variant contain proteins which resemble these emzymes immunologically. (b) We will quantitate the MPS of cultured skin fibroblasts and determine whether they contain the "corrective factors" identified by Neufeld et al. (c) We will study the MPS and oligosaccharide sulfatases in cultured skin fibroblasts from normal individuals and from individuals with variant MLD. 2. Farber's Lipogranulomatosis. We have previously demonstrated accumulation of ceramide in the visceral organs of a patient with this disease. We will attempt to improve the assay of ceramidase activity. Activity of ceramidase and other hydrolytic enzymes will be measured in the tissues of this patient. 3. Cerebrotendinous Xanthomatosis (CTX). Menkes et al. have shown that cholestanol accumulates in CTX. We will study the metabolism of cholesterol and of cholestanol in cultured skin fibroblasts from a patient with CTX. We will examine the role of cholestanol in the nervous system in experimental animals. 4. Lafora Body Epilepsy (LBE). We will study enzymes concerned with glucosan metabolism in cultured skin fibroblasts from a patient with LBE. LBE and normal fibroblasts will be "challenged" with glucosans isolated from Labora bodies.